Cannabinoid receptor modulators

ABSTRACT

Novel pyrazole derivatives are provided which are cannabinoid receptor modulators. ##STR1##

This application is a 371 of PCT/US98/01175 filed Jan. 20, 1998, whichclaims the benefit of provisional application 60/035,073 filed Jan. 21,1997.

FIELD OF THE INVENTION

The present invention relates to novel pyrazole derivatives,pharmaceutical compositions containing these compounds and their use inthe treatment of diseases connected with the modulation of thecannabinoid peripheral receptor.

BACKGROUND OF THE INVENTION

Cannabinoids are a specific class of psychoactive compounds present inIndian cannabis (Cannabis sativa), including about sixty differentmolecules, the most representative being cannabinol, cannabidiol andseveral isomers of tetrahydrocannabinol. Knowledge of the therapeuticactivity of cannabis dates back to the ancient dynasties of China,where, 5,000 years ago, cannabis was used for the treatment of asthma,migraine and some gynaecological disorders. These uses later became soestablished that, around 1850, cannabis extracts were included in the USPharmacopaeia and remained there until 1947.

Cannabinoids are known to cause different effects on various systemsand/or organs, the most important being on the central nervous systemand on the cardiovascular system. These effects include alterations inmemory and cognition, euphoria, and sedation. Cannabinoids also increaseheart rate and vary systemic arterial pressure. Peripheral effectsrelated to bronchial constriction, immunomodulation, and inflammationhave also been observed. The capability of cannabinoids to reduceintraocular pressure and to affect respiratory and endocrine systems isalso well documented. See e.g. L. E. Hollister, Health Aspects ofCannabis, Pharmacological Reviews, Vol. 38, pp. 1-20, (1986). Morerecently, it was found that cannabinoids suppress the cellular andhumoral immune responses and exhibit antiinflammatory properties. Wirthet al., Antiinflammatory Properties of Cannabichrome, Life Science, Vol.26, pp. 1991-1995, (1980).

In spite of the foregoing benefits, the therapeutic use of cannabis iscontroversial, both due to its relevant psychoactive effects (causingdependence and addiction), and due to manifold side effects that havenot yet been completely clarified. Although work in this field has beenongoing since the 1940's, evidence indicating that the peripheraleffects of cannabinoids are directly mediated, and not secondary to aCNS effect, has been limited by the lack of receptor characterization,the lack of information concerning an endogenous cannabinoid ligand and,until recently, the lack of receptor subtype selective compounds.

The first cannabinoid receptor was found to be mainly located in thebrain, in neural cell lines, and, only to a lesser extent, at theperipheral level. In view of its location, it was called the centralreceptor ("CB1"). See Matsuda et al., "Structure of a CannabinoidReceptor and Functional Expression of the Cloned CDNA," Nature, Vol.346, pp. 561-564 (1990. The second cannabinoid receptor ("CB2") wasidentified in the spleen, while being absent at the central location,and was assumed to modulate the non psychoactive effects of thecannabinoids. See Munro et el., "Molecular Characterization of aPeripheral Receptor for Cannabinoids," Nature, Vol. 365, pp. 61-65(1993).

Recently, some compounds have been prepared which are capable of actingas agonists on both the cannabinoid receptors. For example, use ofderivatives of dihydroxypyrrole-(1,2,3-d,e)-1,4-benzoxazine in thetreatment of glaucoma and the use of derivatives of1,5-diphenyl-pyrazole as immunomodultors or psychotropic agents in thetreatment of various neuropathologies, migraine, epilepsy, glaucoma, etcare known. See U.S. Pat. No. 5,112,820 and EP 576357, respectively.However, because these compounds are active on both the CB1 and CB2receptor, they can lead to serious psychoactive effects.

The foregoing indications and the preferential localization of the CB2receptor in the immune system confirms a specific role of CB2 inmodulating the immune and antiinflammatory response to stimuli ofdifferent sources.

The role of CB2 in immunomodulation, inflammation, osteoporosis,cardiovascular, renal and other disease conditions is now beingexamined. In light of the fact that cannabinoids act on receptorscapable of modulating different functional effects, and in view of thelow homology between CB2 and CB1, the importance of developing a classof drugs selective for the specific receptor sub-type is evident. Thenatural or synthetic cannabinoids currently available do not fulfillthis function because they are active on both receptors.

Based on the foregoing, there is a need for compounds which are capableof selectively modulating the peripheral receptor for cannabinoids and,therefore, the pathologies associated with such receptors. Thus, CB2modulators offer a unique approach toward the pharmacotherapy of immunedisorders, inflammation, osteoporosis, renal ischemia and otherpathophysiological conditions.

SUMMARY OF THE INVENTION

The present invention provides novel pyrazole derivatives represented byFormula (I) and pharmaceutical compositions containing these compounds,and their use as CB2 receptor modulators which are useful in thetreatment of a variety of diseases including but not limited to immunedisorder, inflammation, osteoporosis and renal ischemia.

The present invention further comprises a method for modulating CB2receptors in an animal, including humans, which comprises administeringto an animal in need thereof an effective amount of a compound ofFormula (I).

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are represented by structuralFormula (I): ##STR2## wherein: R₁ is OCH₃, Br, isopropyl, or Ar;

R₂ is H, OH, C₁₋₅ alkoxy, C₁₋₅ alkyl, N(R₅)₂, NO₂, Br, F, I, Cl, CF₃, orX(C(R₅)₂)OR₅ ;

R₃ is hydrogen, (CH₂)_(n) XR₅, C(O)R₅, CO₂ R₅, CON(R₅)₂, oxazolinyl,oxazolyl, thiazolyl, pyrazolyl, triazolyl, imidazolyl, tetrazolyl,imidazolinyl, thiazolinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl,each of these heterocyclic rings being unsubstituted or substituted byone or two C₁₋₃ alkyl or fluoroalkyl groups;

R₄ is morpholinyl, piperazinyl or piperidinyl, each moiety beingunsubstituted or substituted by one or two C₁₋₅ alkyl, OH, NO₂ or N(R₅)₂groups;

R₅ is hydrogen or C₁₋₈ alkyl;

X is O or NR₅ ;

Ar is phenyl, anthracenyl, naphthyl, indolyl, pyridinyl, thiophenyl,thiazolyl, isothiazolyl, triazolyl, tetrazolyl, imidazolyl, oxadiazolyl,pyrrolyl or pyrimidinyl; each moiety being unsubstituted or substitutedby one or two Z groups;

Z is H, OH, CO₂ R₅, C₁₋₁₀ alkoxy, C₁₋₅ alkyl, N(R₅)₂, NO₂, Br, F, I, Cl,CF₃, or X(CH₂)_(n) OR₅ ; and

n is 1 to 6;

provided that when n is 1, R₅ is not hydrogen in X(CH₂)_(n) OR₅.

Also included in the present invention are pharmaceutically acceptablesalt complexes. Preferred are the ethylene diamine, sodium, potassium,calcium and ethanolamine salts.

All alkyl and alkoxy groups may be straight or branched. The compoundsof the present invention may contain one or more asymmetric carbon atomsand may exist in racemic and optically active forms. All of thesecompounds and diastereomers are contemplated to be within the scope ofthe present invention.

In preferred compounds of the present invention:

R₁ is C₁₋₅ alkyl or Ar;

R₂ is hydrogen, C₁₋₅ alkyl or Ar;

R₃ is selected from the group consisting of CO₂ R₅, oxazolinyl,tetrazolyl, and oxazolyl, unsubstituted or substituted by one or twoC₁₋₂ alkyl or fluoroalkyl groups;

R₄ is morpholinyl, piperazinyl or piperidinyl, unsubstituted orsubstituted by one or two C₁₋₅ alkyl groups;

R₅ is C₁₋₅ alkyl;

X is O;

Ar is phenyl, unsubstituted or substituted by one or two Z groups; and

n is 2.

In more preferred compounds of the present invention:

R₁ is isopropyl or phenyl, substituted by dichloro, CHO, OCH₂ OCH₃ ; and

R₅ is methyl or ethyl.

Preferred compounds useful in the present invention include ethyl5-(2-morpholin-4-ylethoxy)-1-(4-naphthylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(2-methyl(4-naphthylphenyl))pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate;ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate;5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-oxazoline, ;5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(5-methyl)oxazoline,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole-4-carboxylate,ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazoleand5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylicacid, 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-ylmethanol,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-N,N-dimethylcarbamidate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carbamide,(+/-)-ethyl5-((1-methyl-2-piperidinyl)methoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methyl, ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-bis(trifluoromethyl)phenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-phenylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3-chlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-chlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-formylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,4-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3-aminophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-(4-carboxyphenyl)phenyl)pyrazole-4-carboxylicacid, methyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxycarbonylphenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-N-diethylacetamidephenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-octoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-tert-butyloxycarbomethoxyphenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-benzyloxyphenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methylketone,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-yl-N-ethylcarboxamide,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-carbomethoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-anthracenylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-5-(4-(2-n-butoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,methyl 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,isopropyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,propyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,ethyl5-(2-pyridinylmethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,(R)-(-)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline,(S)-(+)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)oxadiazole,4-methoxymethyl-5-(2-morpholin-4-ylethoxy)-1-(4-(2-methylnaphthyl)phenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-nitrile,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-tetrazole,ethyl5-(4-pyridinylmethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole4(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,ethyl5-(4-pyridinylmethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-ethyl)-tetrazole.

More preferred compounds useful in the present invention include ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate;ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate;ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholinylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-ethyl)-tetrazole,and 5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,(R)-(-)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline,and(S)-(+)-5-(2-morpholin-4ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline.

Even more preferred compounds useful in the present invention includeethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole.

The most preferred compounds useful in the present invention includeethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole.

The present invention provides compounds of Formula (I) above: ##STR3##which can be prepared by a process which comprises:

a) reacting a hydrazine (2), wherein R₁ and R₂ are defined as above,##STR4## with diethyl ethoxymethylenemalonate (3) ##STR5## in thepresence of a base such as potassium carbonate in aqueous solution toform a compound of Formula (4). ##STR6## Mitsunobu reaction of thecompound of Formula (4) with N-hydroxyethyl morpholine (5) ##STR7## inthe presence of triphenylphosphine and diisopropyl azodicarboxylate in asuitable solvent such as tetrahydrofuran provides a compound of Formula(I), wherein R₃ is ethoxycarbonyl group, X is 0, n is 2 and R₄ ismorpholine.

b) Alternatively, in a second synthetic route of the present invention,the product of the Misunobu reaction above is saponified with a basesuch as NaOH in a mixture of ethanol and water followed by treatment ofthe resulting acid with oxalyl chloride in a suitable solvent such asbenzene in presence of a catalytic amount of N,N'-dimethylformamide toafford an acid chloride of Formula (6) ##STR8## Reaction of the acidchloride of Formula (6) with an amino alcohol of Formula (7), wherein Ris C₁₋₆ alkyl, ##STR9## in a suitable solvent such as tetrahydrofuranprovides an oxazoline of Formula (8). ##STR10## Oxidation of theoxazoline of Formula (8) with an oxidant such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone ("DDQ") ortriphenylphosphine-iodine affords an oxazole of Formula (I), where R₃ isan oxazolyl moiety, X is 0, n is 2 and R₄ is morpholine.

c) In a third embodiment of the present invention, treatment of ahydrazine of Formula (2) with ethyl (ethoxyethylene)cyanoacetate ofFormula (9) ##STR11## in the presence of a base such as potassiumcarbonate in aqueous solution provides a compound of Formula (10).##STR12## Alkylation of the compound of Formula (10) with an alkylhalide such as 1-chloro-2-(4-morpholinyl)ethane in presence of a basesuch as potassium carbonate in a suitable solvent such astetrahydrofuran affords a compound of Formula (11). ##STR13## Reactionof the nitrile of Formula (11) with trimethyltin azide in a suitablesolvent such as toluene followed by acidic treatment with hydrochloricacid in methanol provides a tetrazole of Formula (12). ##STR14##Alkylation of the tetrazole of Formula (12) with an alkyl halide such asethyl iodide affords a mixture of ethyl tetrazoles of Formula (I), whereR₃ is ethyl tetrazolyl moiety, X is O, n is 2 and R₄ is morpholine.

With appropriate manipulation and protection of any chemicalfunctionalities, synthesis of the remaining compounds of Formula (I) isaccomplished by methods analogous to those above and to those describedin the Experimental section.

In order to use a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

As used herein, "modulator" means both antagonist and agonist.Preferably the present modulators are antagonists.

As used herein, "treatment" of a disease includes, but is not limited toprevention, retardation and prophylaxis of the disease.

In addition to the conditions listed hereinabove, the present compoundsare useful for the treatment of diseases including but not limited toimmunologically-mediated inflammatory diseases such as rheumatoidarthritis, systemic lupus erythematosus, psoriasis, multiple schlerosis,diabetis and thyroiditis. In addition, the present compounds modulatebone formation/resorption and are useful in the treatment of conditionsincluding but not limited to ankylosing spondylitis, gout, arthritisassociated with gout, osteoarthritis and osteoporosis.

Compounds of Formula (I) and their pharmaceutically acceptable salts maybe administered in a standard manner for the treatment of the indicateddiseases, for example orally, parentarally, sub-lingually, dermally,transdermally, rectally, via inhalation or via buccal administration.

Composition of Formula (I) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as syrups, tablets,capsules and lozenges. A syrup formulation will generally consist of asuspension or solution of the compound or salt in a liquid carrier forexample, ethanol, peanut oil, olive oil, glycerine or water with aflavoring or coloring agent. Where the composition is in the form of atablet, any pharmaceutical carrier routinely used for preparing solidformulations may be used. Examples of such carriers include magnesiumstearate, terra alba, talc, gelatin, acacia, stearic acid, starch,lactose and sucrose. Where the composition is in the form of a capsule,any routine encapsulation is suitable, for example using theaforementioned carriers in a hard gelatin capsule shell. Where thecomposition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates or oils, and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of acompound or salt in a sterile aqueous or non-aqueous carrier optionallycontaining a parenterally acceptable oil, for example polyethyleneglycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

Typical compositions for inhalation are in the form of a solution,suspension or emulsion that may be administered as a dry powder or inthe form of an aerosol using a conventional propellant such asdichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (I) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogs.

Typical dermal and transdermal formulations comprise a conventionalaqueous or non-aqueous vehicle, for example a cream, ointment, lotion orpaste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet,capsule or metered aerosol dose, so that the patient may administer asingle dose.

Each dosage unit for oral administration contains suitably from 0.1 mgto 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosageunit for parenteral administration contains suitably from 0.1 mg to 100mg/Kg, of a compound of Formula(I) or a pharmaceutically acceptable saltthereof calculated as the free acid. Each dosage unit for intranasaladministration contains suitably 1-400 mg and preferably 10 to 200 mgper person. A topical formulation contains suitably 0.01 to 5.0% of acompound of Formula (I).

The daily dosage regimen for oral administration is suitably about 0.01mg/Kg to 40 mg/Kg, of a compound of Formula(I) or a pharmaceuticallyacceptable salt thereof calculated as the free acid. the daily dosageregimen for parenteral administration is suitably about 0.001 mg/Kg to40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof calculated as the free acid. the daily dosage regimen forintranasal administration and oral inhalation is suitably about 10 toabout 500 mg/person. The active ingredient may be administered from 1 to6 times a day, sufficient to exhibit the desired activity.

No unacceptable toxicological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention.

The biological activity of the compounds of Formula (I) are demonstratedby the following tests:

Human CB2 Cannabinoid Receptor Binding Assay

HEK 293 cells, stably transfected with the human CB2 receptor are scaledup as follows. CB2 membrane is made from polyclonal CB2 receptorsexpressing 293 cells. The assay buffer comprises 50 mM Tris (pH 7.5), 5mM MgCl2, 2.5 mM EDTA and 5 mg/ml fatty-acid free Bovine Serum Albumin.All chemicals utilized are obtained from Sigma, except fatty acid-freeBovine Albumin Fraction V, which is from CalBiochem, and tritiated5-(1,1-dimethylheptyl)-2-(5-hydroxypropyl)cyclohexyl)-1 alpha, 2 beta, 5alpha)-phenol ("³ H-CP 55,940") (103.4 Ci/mmol, 1 m Ci/ml), which isfrom DuPont NEN. All compounds are dissolved in DMSO.

The final compound concentrations range from 1.00 E⁻⁴ to 1.00E⁻¹⁰. Thereaction mixture is obtained by combining 1.3-1.8 nM ³ H-CP 55,940, in areaction volume of 150 μl, and 50 μg membrane in homogenization buffercontaining fatty acid-free BSA. A 96 deep well microtiter polypropyleneplate is utilized. 50 μl ³ H-CP 55,940 stock solution are added threetimes to each well of the microtiter plate. 45 μl assay buffer are addedto the total number of binding samples, followed by 45 μl of 1 μM cold ³H-CP 55,940 to non-specific samples. 5 μl of each concentration ofcompound are added to the 96 deep well plate except the designated totaland non-specific wells. 5 μl DMSO are added manually for the total andnon-specific wells.

The binding reaction is initiated by the addition of 50 μl of 20 μg perwell of CB2 membrane. The reaction mixture is incubated for one hour at30° C. in a shaking water bath. The binding reaction is terminated byrapid filtration onto GF/B filter paper treated with wash buffer using aBrandel 96-well cell harvester, followed by washing five times with 3 mlice-cold wash buffer. The filters are air dried, placed in scintillationfluid and ³ H-CP 55,940 radioactivity determined by liquid scintillationcounting. Competition binding curves are analyzed by non-linearregression using GRAPHPAD PRISM. K_(i) values ranging from 25 nM to 10μM are obtained for the antagonists of the present invention.

The following examples are illustrative, but not limiting of theembodiments of the present invention.

EXAMPLE 1

Ethyl5-(2-morpholin-4-ylethoxy)-1-[4-(2-formylphenyl)phenyl]pyrazole-4-carboxylate

a) Ethyl 1-(4-bromophenyl)-4-pyrazolin-5-one carboxylate

A solution of 4-bromophenylhydrazine hydrochloride (15.00 g, 0.07 mol),potassium carbonate (30.00 g, 0.20 mol) and diethyl ethoxymethylenemalonate (20.00 ml, 0.08 mol) in water (250 mL) was stirred at refluxfor 18 h. Extraction with ethyl acetate (3×100 mL), washing the combinedorganics with 10% HCl solution, gave a crude oil. Purification by flashchromatography of the oil (silica gel, 25% ethyl acetate/hexane)afforded the title compound as a brown solid (19.70 g, 93%). ¹ H NMR(250 MHz, CDCl₃) d 7.74 (s, 1H), 7.58-7.62 (d, 1H), 7.36-7.42 (d, 1H),5.35 (s, 1H), 4.40 (q, 2H), 1.33 (t, 3H). MS(ESI) m/e 311.1 [M+H]⁺ ; mp:164° C. (methanol).

b) Ethyl5-(2-morpholin-4-ylethoxy)-1-(4-bromophenyl)pyrazole-4-carboxylate

A solution of ethyl 1-(4-bromophenyl)-4-pyrazolin-5-one carboxylate(18.10 g, 0.06 mol), triphenylphosphine (20.00 g, 0.08 mol), diisopropylazodicarboxylate (15.00 μL, 0.08 mol) and 4-(2-hydroxyethyl)morpholine(8.50 mL, 0.07 mol) in THF (250 mL) was stirred at reflux for 5 h. Thereaction was quenched with water and extracted with ethyl acetate. Theorganic extract was washed with brine and dried (Na₂ SO₄). Afterremoving the solvent, flash chromatography of the residue (silica gel,50% ethyl acetate/hexane) afforded the title compound as a brown oil(19.50 g, 79%). ¹ H NMR (250 MHz, CDCl₃) d 7.90 (s, 1H), 7.62 (d, 1H),7.52 (d, 1H), 4.55 (t, 2H), 4.35 (q, 2H), 3.52 (t, 4H), 2.61 (t, 2H),2.28 (t, 4H), 1.35 (t, 3H). MS(ESI) m/e 424.3 [M+H]⁺.

c) Ethyl5-(2-morpholin-4-ylethoxy)-1-[4-(2-formylphenyl)phenyl]pyrazole-4-carboxylate

A mixture of ethyl5-(2-morpholin-4-ylethoxy)-1-(4-bromophenyl)pyrazole-4-carboxylate (0.25g, 0.59 mmol), sodium carbonate (0.20 g, 1.77 mmol),tetrakis(triphenylphosphine) palladium (0) (0.12 g, 0.18 mmol) and1-formylbenzeneboronic acid (0.10 g, 0.76 mmol) in a solution of toluene(10 mL), ethanol (1 mL) and water (1 mL) was stirred at reflux for 18 h.The reaction was diluted with water and extracted with ethyl acetate.The organic extract was washed with brine and dried (Na₂ SO₄). Afterremoving the solvent, flash chromatography of the residue (silica gel,50% ethyl acetate/hexane) afforded the title compound as an oil (0.14 g,66%). ¹ H NMR (250 MHz, CDCl₃) d 9.98 (s, 1H), 8.01 (d, 1H), 7.92 (s,1H), 7.85 (d, 2H), 7.62 (d, 1H), 7.46 (m, 4H), 4.65 (t, 2H), 4.35 (q,2H), 3.56 (t, 4H), 2.68 (t, 2H), 2.38 (t, 4H), 1.38 (t, 3H). MS(ESI) m/e450.4 [M+H]⁺.

EXAMPLES 2-63

The following compounds are synthesized according to the methods ofExample 1:

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-naphthylphenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylicacid,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-yl methanol,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-N,N-dimethylcarbamidate,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carbamide,

(+/-)-ethyl5-((1-methyl-2-piperidinyl)methoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methyl, ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-bis(trifluoromethyl)phenyl)-phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-phenylphenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-dichlorophenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3-chlorophenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-chlorophenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-formylphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,4-dichlorophenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methylphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3-aminophenyl)phenyl)pyrazole-4-carboxylate,

5-(2-morpholin-4-ylethoxy)-1-(4-(4-carboxyphenyl)phenyl)pyrazole-4-carboxylicacid,

methyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxycarbonylphenyl)-phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-N-diethylacetamidephenyl)-phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-octoxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-tert-butyloxycarbomethoxyphenyl)-phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-benzyloxyphenyl)phenyl)pyrazole-4-carboxylate,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methylketone,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-yl-N-ethylcarboxamide,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-carbomethoxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-anthracenylphenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-n-butoxyphenyl)phenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,

methyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

isopropyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

propyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

ethyl5-(2-pyridinylmethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-oxazoline,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(5-methyl)oxazoline,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)oxadiazole,

4-methoxymethyl-5-(2-morpholin-4-ylethoxy)-1-(4-(2-methylnaphthyl)phenyl)-pyrazole,

5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole,

5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-nitrile,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-tetrazole,

a mixture of5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazoleand5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,

ethyl5-(4-pyridinylmethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,

5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-tetrazole,

a mixture of5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazoleand5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,

ethyl5-(4-pyridinylmethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate, and

ethyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate.

Formulations for pharmaceutical use incorporating compounds of thepresent invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.

EXAMPLE 64

Inhalant Formulation

A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metereddose inhaler to deliver the desired amount of drug per use.

EXAMPLE 65

    ______________________________________                                        Tablet Formulation                                                            Tablets/Ingredients      Per Tablet                                           ______________________________________                                        1.     Active ingredient (Cpd of Form. I)                                                               40        mg                                        2.     Corn Starch        20        mg                                        3.     Alginic acid       20        mg                                        4.     Sodium Alginate    20        mg                                        5.     Mg stearate        1.3       mg                                                                  2.3       mg                                        ______________________________________                                    

Procedure for tablet formulation:

Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender.Sufficient water is added portion-wise to the blend with careful mixingafter each addition until the mass is of a consistency to permit itsconversion to wet granules. The wet mass is converted to granules bypassing it through an oscillating granulator using a No. 8 mesh (2.38mm) screen. The wet granules are then dried in an oven at 140° F. (60°C.) until dry. The dry granules are lubricated with ingredient No. 5,and the lubricated granules are compressed on a suitable tablet press.

EXAMPLE 66

Parenteral Formulation

A pharmaceutical composition for parenteral administration is preparedby dissolving an appropriate amount of a compound of formula I inpolyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is then renderedsterile by filtration through a 0.22 micron membrane filter and sealedin sterile containers.

All publications, including but not limited to patents and patentapplications cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference as though fullyset forth.

What is claimed is:
 1. A compound of formula (I): ##STR15## wherein: R₁is OCH₃, Br, isopropyl, or Ar;R₂ is H, OH, C₁₋₅ alkoxy, C₁₋₅ alkyl,N(R₅)₂, NO₂, Br, F, I, Cl, CF₃, or X(C(R₅)₂)OR₅ ; R₃ is hydrogen,(CH₂)_(n) XR₅, C(O)R₅, CO₂ R₅, CON(R₅)₂, oxazolinyl, oxazolyl,thiazolyl, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, imidazolinyl,thiazolinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, each of theseheterocyclic rings being unsubstituted or substituted by one or two C₁₋₃alkyl or fluoroalkyl groups; R₄ is morpholinyl, piperazinyl orpiperidinyl, each moiety being unsubstituted or substituted by one ortwo C₁₋₅ alkyl, OH, NO₂ or N(R₅)₂ groups; R₅ is hydrogen or C₁₋₈ alkyl;X is O or NR₅ ; Ar is phenyl, anthracenyl, naphthyl, indolyl, pyridinyl,thiophenyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, imidazolyl,oxadiazolyl, pyrrolyl or pyrimidinyl; each moiety being unsubstituted orsubstituted by one or two Z groups; Z is H, OH, CO₂ R₅, C₁₋₁₀ alkoxy,C₁₋₅ alkyl, N(R₅)₂, NO₂, Br, F, I, Cl, CF₃, or X(CH₂)_(n) OR₅ ; and n is1 to 6; andpharmaceutically acceptable salts thereof; provided that whenn is 1, R₅ is not hydrogen in X(CH₂)_(n) OR₅.
 2. A compound according toclaim 1 wherein:R₁ is C₁₋₅ alkyl or Ar; R₂ is hydrogen, C₁₋₅ alkyl orAr; R₃ is selected from the group consisting of CO₂ R₅, oxazolinyl,tetrazolyl, and oxazolyl, unsubstituted or substituted by one or twoC₁₋₂ alkyl or fluoroalkyl groups; R₄ is morpholinyl, piperazinyl orpiperidinyl, unsubstituted or substituted by one or two C₁₋₅ alkylgroups; R₅ is C₁₋₅ alkyl; X is O; Ar is phenyl, unsubstituted orsubstituted by one or two Z groups; and n is
 2. 3. A compound accordingto claim 1 wherein:R₁ is isopropyl or phenyl substituted by dichloro,CHO, OCH₂ OCH₃ ; and R₅ is methyl or ethyl.
 4. A compound according toclaim 1 selected from the group consisting of:ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-naphthylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylicacid, 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-ylmethanol,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-N,N-dimethylcarbamidate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carbamide,(+/-)-ethyl5-((1-methyl-2-piperidinyl)methoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methyl, ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-bis(trifluoromethyl)phenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-phenylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3-chlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-chlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-formylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,4-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(3-aminophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-(4-carboxyphenyl)phenyl)pyrazole-4-carboxylicacid, methyl5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxycarbonylphenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-N-diethylacetamidephenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-octoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-tert-butyloxycarbomethoxyphenyl)-phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-benzyloxyphenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methylketone,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-yl-N-ethylcarboxamide,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-carbomethoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-anthracenylphenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-n-butoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,methyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,isopropyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,propyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-oxazoline,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(5-methyl)oxazoline,(R)-(-)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline,(S)-(+)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)oxadiazole,4-methoxymethyl-5-(2-morpholin-4-ylethoxy)-1-(4-(2-methylnaphthyl)phenyl)-pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-nitrile,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-methyl)-tetrazole,and ethyl5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate.5. A compound according to claim 1 selected from the group consistingof:ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate;ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate;ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole.6. A compound according to claim 1 selected from the group consistingof:ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-ethyl)-tetrazole.7. A compound according to claim 1 selected from the group consistingof:ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,ethyl5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,and5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole.8. A pharmaceutical composition comprising a compound according to claim1 and a pharmaceutically acceptable carrier.
 9. A method of antagonizingcannabinoid 2 receptors which comprises administering to a subject inneed thereof, an effective amount of a compound of claim
 1. 10. A methodof treatment of diseases caused by an excess of cannabinoid comprisingadministering to a subject in need thereof an effective amount of acannabinoid receptor 2 antagonist according to claim
 1. 11. A method oftreating an immunologically-mediated inflammatory disease selected fromthe group consisting of rheumatoid arthritis, systemic lupuserythematosus, psoriasis, multiple sclerosis, diabetes and thyroiditiswhich comprises administering to a subject in need thereof an effectiveamount of a compound according to claim
 1. 12. A method of treating adisease selected from the group consisting of ankylosing spondylitis,gout, gouty arthritis, osteoarthritis and osteoporosis which comprisesadministering to a subject in need thereof an effective amount of acompound according to claim
 1. 13. A method of treating renal ischemiawhich comprises administering to a subject in need thereof an effectiveamount of a compound according to claim 1.